Lithium isotopes differentially modify mitochondrial amorphous calcium phosphate cluster size distribution and calcium capacity

Marshall L Deline; Joshua Straub; Manisha Patel; Pratigya Subba; Martin Grashei; Frits H A van Heijster; Philip Pirkwieser; Veronika Somoza; James D Livingstone; Michael Beazely; Brian Kendall; Michel J P Gingras; Zoya Leonenko; Carmen Höschen; Gertraud Harrington; Katharina Kuellmer; Wangqing Bian; Franz Schilling; Matthew P A Fisher; Matthew E Helgeson; Tobias Fromme

doi:10.3389/fphys.2023.1200119

Lithium isotopes differentially modify mitochondrial amorphous calcium phosphate cluster size distribution and calcium capacity

Front Physiol. 2023 Sep 15:14:1200119. doi: 10.3389/fphys.2023.1200119. eCollection 2023.

Authors

Marshall L Deline¹, Joshua Straub², Manisha Patel², Pratigya Subba¹, Martin Grashei³, Frits H A van Heijster³, Philip Pirkwieser⁴, Veronika Somoza^{4

5}, James D Livingstone⁶, Michael Beazely⁶, Brian Kendall⁷, Michel J P Gingras^{8

9}, Zoya Leonenko^{8

10}, Carmen Höschen¹¹, Gertraud Harrington¹¹, Katharina Kuellmer¹, Wangqing Bian¹, Franz Schilling³, Matthew P A Fisher², Matthew E Helgeson¹², Tobias Fromme^{1

13}

Affiliations

¹ Chair of Molecular Nutritional Medicine, TUM School of Life Sciences, Technical University of Munich, Freising, Germany.
² Department of Physics, University of California, Santa Barbara, CA, United States.
³ Department of Nuclear Medicine, TUM School of Medicine, Technical University of Munich, Munich, Germany.
⁴ Leibniz Institute for Food Systems Biology at the Technical University of Munich, Freising, Germany.
⁵ Chair of Nutritional Systems Biology, TUM School of Life Sciences, Technical University of Munich, Munich, Germany.
⁶ School of Pharmacy, University of Waterloo, Waterloo, ON, Canada.
⁷ Department of Earth and Environmental Sciences, University of Waterloo, Waterloo, ON, Canada.
⁸ Department of Physics and Astronomy, University of Waterloo, Waterloo, ON, Canada.
⁹ CIFAR, MaRS Centre, Toronto, ON, Canada.
¹⁰ Department of Biology, University of Waterloo, Waterloo, ON, Canada.
¹¹ Chair of Soil Science, TUM School of Life Sciences, Technical University of Munich, Munich, Germany.
¹² Department of Chemical Engineering, University of California, Santa Barbara, CA, United States.
¹³ EKFZ-Else Kröner-Fresenius Center for Nutritional Medicine, Technical University of Munich, Freising, Germany.

Abstract

Lithium is commonly prescribed as a mood stabilizer in a variety of mental health conditions, yet its molecular mode of action is incompletely understood. Many cellular events associated with lithium appear tied to mitochondrial function. Further, recent evidence suggests that lithium bioactivities are isotope specific. Here we focus on lithium effects related to mitochondrial calcium handling. Lithium protected against calcium-induced permeability transition and decreased the calcium capacity of liver mitochondria at a clinically relevant concentration. In contrast, brain mitochondrial calcium capacity was increased by lithium. Surprisingly, ⁷Li acted more potently than ⁶Li on calcium capacity, yet ⁶Li was more effective at delaying permeability transition. The size distribution of amorphous calcium phosphate colloids formed in vitro was differentially affected by lithium isotopes, providing a mechanistic basis for the observed isotope specific effects on mitochondrial calcium handling. This work highlights a need to better understand how mitochondrial calcium stores are structurally regulated and provides key considerations for future formulations of lithium-based therapeutics.

Keywords: amorphous calcium phosphate; calcium; isotope distribution; lithium; lithium bioactivity; mitochondria; mitochondrial calcium.

Copyright © 2023 Deline, Straub, Patel, Subba, Grashei, van Heijster, Pirkwieser, Somoza, Livingstone, Beazely, Kendall, Gingras, Leonenko, Höschen, Harrington, Kuellmer, Bian, Schilling, Fisher, Helgeson and Fromme.

Grants and funding

The contributions of MD, TF, JS, MP, MH, and MF were funded with Science Program grants by the Heising-Simons Foundation (#2017-0496 and #2020-2427). This study was in part funded by a research grant by IONIS Pharmaceuticals, United States, to MF, TF, MiG, ZL, and MH. JL, MiG, and ZL were funded by Transformative Quantum Technologies Seed Grant, University of Waterloo and New Frontiers in Research Fund (NFRF) grant. MiG and BK were supported by Canada Research Chairs program. FS, MaG, and FH were supported by the Deutsche Forschungsgemeinschaft (DFG, German Research Foundation—391523415—SFB 824, subprojects A7), the Young Academy of the Bavarian Academy of Sciences and Humanities and the European Union’s Horizon 2020 research and innovation program (Grant agreement 820374). KK and TF are funded by the Deutsche Forschungsgemeinschaft (DFG, German Research Foundation—TRR 333/1—450149205). WB is supported by a scholarship of the Oversea Study Program of the Guangzhou Elite Project. TF is supported by the Else Kröner-Fresenius Stiftung (EKFS).